Thus, blocking the TRAIL–TRAIL-R2 interaction may be beneficial for patients with KRAS-mutated cancers by acting on three levels: (i) by blocking cell-autonomous Rac1 activation; (ii) through inhibiting the creation of a type 2 macrophage-conducive TIME; and (iii) by prolonging CD8 T-cell activation, allowing for an increased level of “auto-reactive” immunity functionally similar to, but, importantly, molecularly distinct from, conventional ICB (concepts summarized in Fig. 3). This evidence concerns the gene TNFSF10 and cancer.